Ion trap mass analyzers have been described extensively in the literature (see, e.g., March et al., “Quadrupole Ion Trap Mass Spectrometry”, John Wiley & Sons (2005)) and are widely used for mass spectrometric analysis of a variety of substances, including small molecules such as pharmaceutical agents and their metabolites, as well as large biomolecules such as peptides and proteins. Mass analysis is commonly performed in ion traps by the mass-selective resonance ejection method, which has been widely practiced since the late 1980's (e.g., U.S. Pat. No. 4,736,101, titled “Method of operating ion trap detector in MS/MS mode”). In this method, ions of various mass are brought sequentially into resonance with a weak supplementary dipolar AC resonant ejection voltage, Vreseject. Ions in the trap oscillate with a frequency that depends on the amplitude of the main radio-frequency (RF) trapping voltage VRF. Typically, in the resonance ejection method, after application of the resonance ejection voltage, Vreseject, masses are then brought sequentially into resonance by ramping the trapping voltage amplitude, VRF, thereby causing the ions to be ejected from the ion trap to the detector(s) in order of their masses (or mass-to-charge ratios—m/z's). If VRF is varied at a constant rate, then the derivative of mass of ejected ions with respect to time at a particular frequency is nominally constant, and ions of successive mass will be ejected at constant time intervals, i.e. the mass scale will be linear.
In practice, the mass scale of resonantly ejected ions is only approximately linear with respect to VRF when an ion trap is operated as described above. The deviations from linearity are especially pronounced at high rates of scanning VRF. Since scanning an ion trap at very fast rates with good mass accuracy is a desirable goal, an improved means of operating the trap or correcting the data post-acquisition is required.
Moreover, one is often principally concerned, in terms of choosing resonant ejection voltage amplitude, with ejecting ion packets having optimal peak characteristics (e.g., U.S. Pat. No. 7,804,065, titled “Methods of calibrating and operating an ion trap mass analyzer to optimize mass spectral peak characteristics” in the names of inventors Remes et al., incorporated herein by reference in its entirety), and then subsequently linearizing the mass scale. Thus, an additional instrument metric of interest is the set of characteristics which comprise a well-formed peak (U.S. Pat. No. 7,804,065). That is to say, the resonant ejection voltage should be scanned with mass in a way that optimizes the shape of the peak. As used herein, peak quality is a value calculated from one or more peak characteristics such as peak height, width, inter-peak valley depth, peak symmetry, spacing of related peaks representing an isotopic distribution and peak position and is representative of the ability of the peak to provide meaningful and accurate qualitative and/or quantitative information regarding the associated ion. The peak quality may be calculated from a set of equations stored in the memory of a control and data system. The peak quality may be calculated in a different fashion for each scan rate.
It is known that the characteristics and quality of a mass spectral peak acquired by resonant ejection will vary with the amplitude of the resonant ejection voltage, and that the amplitude that optimizes certain peak characteristics depends on the m/z of the ejected ion. The prior art contains a number of references that describe methods for varying the resonant ejection voltage amplitude during an analytical scan in order to produce high quality mass spectral peaks across the measured range of m/z's. For example, U.S. Pat. No. 5,298,746 to Franzen et al. (“Method and Device for Control of the Excitation Voltage for Ion Ejection from Ion trap Mass Spectrometers”) prescribes controlling the resonant ejection voltage during the analytical scan such that its amplitude is set proportionally to the square root of the main RF trapping voltage amplitude. In another example, U.S. Pat. No. 5,572,025 to Cotter et al. discloses operating an ion trap to maintain a constant ratio between the RF trapping voltage and resonant ejection voltage amplitudes. As another example, the instant inventors, in the aforementioned U.S. Pat. No. 7,804,065, described a method for calibrating an ion trap mass spectrometer including steps of: selecting a phase of the resonant ejection voltage that optimizes a peak quality representative of one or more mass spectral peak characteristics; identifying, for each of a plurality of calibrant ions having different m/z's, a resonant ejection voltage amplitude that optimizes the peak quality when the ion trap is operated at the selected phase; and, deriving a relationship between m/z and resonant ejection voltage amplitude based on the optimized resonant ejection voltage amplitude identified for the plurality of calibrant ions.
Many commercially available ion trap mass spectrometers utilize a calibration procedure in which the resonant ejection voltage amplitude that optimizes one or more peak characteristics (e.g., peak width) is experimentally determined for each of several calibrant ions having different m/z's, and an amplitude calibration is developed by fitting a line to the several (m/z, amplitude) points. Conventionally, it is considered that, to a first approximation, the optimal resonant ejection voltage should be linear with mass, so that ions of each mass have identical rates of approaching the resonance frequency. In practice, however, deviations from linearity are observed, especially at high scan rates. Thus, deviations from linearity are observed not only in the form of the mass dependency of the optimal resonance ejection voltage, but also in the form of the mass dependency of the scanned trapping voltage. Thus, the methods of calibrating and operating the ion trap should also take into account such deviations from linearity of applied voltages, especially as they relate to different scanning rates.